tbuckley/cabot-search huggingface dataset:
NIMG-39. BENCHMARKING MULTI-LABEL PREDICTION OF TARGET GENE MUTATION STATUS IN GLIOBLASTOMA USING RADIOGENOMICS AND MULTI-PARAMETRIC MR IMAGING
Authors: Fanyang Yu, Jun Guo, Anahita Fathi Kazerooni, Hamed Akbari, Erik Toorens, Chiharu Sako, Elizabeth Mamourian, Stephen J Bagley, Zev Binder, Robert A Lustig, Steven Brem, Donald M O'Rourke, Tapan Ganguly, Spyridon Bakas, MacLean P Nasrallah, Pratik Chaudhari, Christos Davatzikos
Journal: Neuro-Oncology (2023)

Abstract PURPOSE In vivo imaging-based prediction of gene mutation status can significantly contribute to the diagnosis and treatment of glioblastoma. Radiogenomics provides a non-invasive approach to capturing the phenotypical characteristics of molecular alterations. We build machine learning (ML) models on radiogenomics and MR imaging data for benchmarking the prediction of multiple target genes in a single institution dataset. METHODS Multi-parametric MRI scans (T1, T1-Gd, T2, T2-FLAIR, DSC, DTI) of 286 individuals with glioblastoma were used to extract radiomics features, including histograms, morphological and textural descriptors. Genetic markers were obtained through a targeted next generation sequencing panel. We built ML models to predict mutation status in two settings: (a) 4 frequently-occurring mutations (EGFR, PTEN, NF1, TP53), (b) 13 mutations including some that are infrequent (PDGFRA, MET, FGFR2, PIK3CA, PIK3R1, BRAF, MDM4, CDKN2A). The models include k-nearest neighbor classifiers, fully-connected neural networks w/o dimensionality reduction trained on radiomics data, convolutional (CNN) and self-attention-based (ViT) networks trained on MR imaging data. All models were trained with 5-fold cross validation on discovery cohort (n=257) and tested on replication cohort (n=29). RESULTS Multi-label prediction models achieved highest accuracies of 75.9% / 88.6% for 4 / 13 mutations using radiomics features. Models trained with radiomics features have a marginally better average F1 score than CNNs and ViTs trained on MR imaging data (by 4.1% / 4.6% for 4 / 13 mutations). CONCLUSION We had modest success in finding highly distinct MR signatures of multiple target mutations in glioblastoma using multi-label ML methods, presumably because of the small sample size and the molecular, the spatial heterogeneity of the tumor, and the difficulty of simultaneously learning multiple imaging signatures. This highlights the importance of pooling and harmonizing radiogenomics data from multiple institutions to increase the sample size, and of incorporating biological domain knowledge into ML models.
STEM-02. SYNGN: A NOVEL EPIGENETIC PLATFORM FOR PATIENT-SPECIFIC DRUG-MATCHING IN GLIOBLASTOMA
Authors: Claire Vinel, James Boot, Radu Zabet, Sebastian Brandner, Silvia Marino
Journal: Neuro-Oncology (2023)

Abstract The alteration of the glioblastoma genome by epigenetic mechanisms that share functions with normal developmental processes, such as self-renewal and fate specification of NSC, is a key piece of evidence that links brain cancer pathogenesis with dysregulated stem cell functions. A patient-specific comparison of glioblastoma cells with NSC, a putative cell of origin of at least a proportion of these tumours, is not feasible as patient-matched endogenous NSC are not surgically accessible and all epigenetic studies in glioblastoma have so far compared epigenetic changes of different tumours with each other or to comparators obtained from foetal brains or an unrelated donor. We reasoned that availability of syngeneic GSC and NSC pairs would allow to identify crucial epigenetic differences on a patient-specific basis and would provide essential therapeutic contrast to define disease-and patient-intrinsic biomarkers of drug response that are less confounded by germline variation. We have derived GSC from IDH-wildtype glioblastoma and harnessed state-of-the-art stem cell technologies to generate patient-matched fibroblast-derived EPSC, which were induced to NSC (iNSC). We demonstrate that integrated analysis of the transcriptome and DNA methylome of GSC/iNSC pairs identifies druggable target genes (PTGER4, ALDH3B1, NTRK2) in a proportion of patients and we validate this patient-specific prediction of drug response at pre-clinical level in 3D synGLICO and in in vivo models. Integration of small RNA regulation to the pipeline allows refined in silico prediction of drug responses on a patient-specific basis. Most recently we have added assessment of chromatin remodelling (H3K4me3, H3K27ac, H3K3me3, H3K27me3 and ATACSeq) to the pipeline and shown that redistribution of selected histone marks as well as shifts in chromatin states across the genome identifies known and novel druggable regulatory mechanisms in GSC, which are specific of the neoplastic context. In conclusion, SYNGN is an epigenetic platform which can identify patient-specific druggable targets in glioblastoma.
RADT-06. IMPACT OF STATUS OF TUMOR PROGRESSION PRIOR TO STEREOTACTIC RADIOSURGERY ON LOCAL TUMOR CONTROL IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Reema Patel, Zhiyuan Xu
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Prognosis in patients triple-negative breast cancer (TNBC) brain metastases remains poor owing to the lack of treatment targeting pathways. Furthermore, approaches–like surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy–have variable efficacy depending on the degree of tumor burden. The cohort of patients benefit least to targeted therapy and immunotherapy, therefore, forming ideal candidates to evaluate the local tumor control attributed to SRS. This study aimed to characterize intracranial tumor response and clinical outcomes in the patient cohort. PATIENTS and METHODS This retrospective, single-center study included patients with confirmed TNBC brain metastases treated with SRS at the University of Virginia Health. Tumor response, new intracranial tumor development, and survival were investigated. 24 patients with 169 total treated lesions between 2007 and 2021 were assessed. The median age of patients at the initial treatment was 49.1 years. RESULTS One MRI within one month prior to SRS plus the treatment study MRI were evaluated. Tumor progression at the time of SRS led to worse local tumor control following the first SRS treatment (p &amp;lt; 0.0001). 15.1% of total treated lesions demonstrated a complete response, while 48.5% had a partial response. 25.7% of lesions remained stable and 13.5% progressed. Three patients did not have any follow-up imaging to assess initial tumor response due to mortality. For patients with tumor progression, the progression-free survival was 4.93 months. Additionally, new intracranial metastases developed in ten patients over their treatment course. Median overall survival following the first SRS session was 9.83 months (range 0.9 - 37.7 months), with a 1-year and 2-year survival of 54.5% and 22.7%, respectively. CONCLUSION Tumor control in patients with TNBC treated with SRS is unfavorable. Tumor progression prior to SRS might lead to worse tumor control. Further study is warranted to evaluate this phenomenon in a large cohort of patients.
BIOM-30. CELL LINE STUDY OF NUCLEOSOME-BASED BIOMARKERS IN THE DIAGNOSIS AND DETECTION OF RELAPSES IN GLIOBLASTOMA
Authors: Jonathan Decarpentrie, Priscilla Van den Ackerveken, Adrien Govaerts, Alison Lobbens, Edeline Beine, Nathalie Donis, Marielle Herzog, Jonathan Douxfils
Journal: Neuro-Oncology (2023)

Abstract Currently, glioblastoma (GBM) diagnosis and monitoring rely on neuroimaging and histopathological confirmation. However, overall survival has not improved in last decades due to therapeutic failure and to a lack of biomarkers for relapses’ detection. Liquid biopsies (i.e. blood or CSF) using nucleosomes-containing-histone post-translational modifications (PTMs) have the potential to become valuable biomarkers for diagnosis and monitoring GBM. Four glioblastoma cell lines (SF-126, U-87MG, U-118MG, and U-138MG) compared to a healthy microglia cell line (HMC3) and other solid cancer cell lines including pancreas (MIA-PaCa-2), liver (HepG2), and cervix/uterus (HeLa) have been analyzed to identify their epigenetic profile. Nucleosomes were extracted and analyzed with the Nu.Q® Discover immunoassays platform addressing 13 histone-PTMs. Quantitative results of PTMs expression were normalized on quantification of total H3.1-nucleosomes. The immunoassay identified three candidate biomarkers compared to control cell lines (n = 4): citrullinated-histone-H3 (H3R8Cit) (control = 4.68%; GBM = 13.88%; p&amp;lt; 0.05), phosphorylation of H3S10 (H3S10Ph) (control = 2.31%; GBM = 5.57%; p&amp;lt; 0.05), and a trend in H3K4Me2 elevation (control = 0.43%; GBM = 1.07%; p = 0.066) in GBM cell lines (n = 4). These results were confirmed by western blot. Moreover, principal component analysis revealed a segregation between GBM and control cells, mainly driven by these three PTMs. Moreover, to demonstrate the capacity of the Nu.Q® assays to quantitatively monitor PTMs, GBM cell line SF-126 (n = 3) was treated with an EZH2 inhibitor (responsible of H3K27 methylation) (iEZH2). After 24 hours and 48 hours of exposure, the expression level of H3K27Me3 –expressed as ratio of total nucleosomes– was decreased by 32% (control = 14.67%±0.58%; iEZH2= 10.00%±1.73%; p&amp;lt; 0.05) and 41% (control = 15.33%±1.53%; iEZH2= 9.00%±0.00%; p&amp;lt; 0.05), respectively. Those results were also confirmed by western blot analysis. In conclusion, we identified three specific in vitro epigenetic-based marks of GBM and demonstrated that the Nu.Q® technology is a valuable tool to monitor the degree of PTMs expression.
QOL-12. NEURO-ONCOLOGY INCLUSION IN PSYCHOTHERAPEUTIC INTERVENTION TRIALS: LEARNING WHICH COGNITIVE ADAPTATIONS COULD SUPPORT PATIENT ENGAGEMENT?
Authors: Ashlee Loughan, Autumn Lanoye, Sarah Braun, Amber Fox, Giuliana Zarrella
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Many patients with brain tumors experience double vulnerability—significant emotional distress coupled with cognitive decline—however, these cognitive changes often prohibit their inclusion in psychotherapeutic interventions that might otherwise improve their wellbeing. The primary goal of this analysis was to understand how best to accommodate the neurocognitive needs of patients with brain tumors so that they may effectively participate in future psychotherapeutic interventions. Our secondary goal was to assess potential differences in desired cognitive adaptations between patients with primary compared to metastatic brain tumors. METHODS In two recently completed Phase 2 proof-of-concept trials, patients with both primary and metastatic brain tumors (N = 27) participated in a 3-month psychotherapeutic intervention, Managing Cancer and Living Meaningfully (CALM). During exit interviews, participants reported whether evidence-informed accommodations would support their cognitive limitations and enhance engagement in future trials. Additionally, trial interventionists identified which accommodations were used in each session. RESULTS Participants recommended several accommodations: appointment reminders (100%), topic refreshers (94%), prior session summaries (88%), visual handouts (82%), time for consolidation (71%), transcription notepads (65%), and questionnaire completion assistance (24%). Interventionists documented using appointment reminders (66%), topic refreshers (53%), prior session summaries (60%), and time for consolidation (60%) in more than half of sessions. Visual handouts (2%), notepads (0%), and questionnaire assistance (17%) were rarely or never used. CONCLUSIONS: RESULTS were similar across the two brain tumor populations surveyed: primary and metastatic brain tumors. Accommodations that were recommended by patients and used by interventionists included: (1) appointment reminders to support session attendance, (2) topic refreshers and prior session summaries to support memory, and (3) additional time to assist with slower processing and support comprehension. Implementing supportive cognitive strategies is vital when promoting neuro-oncology inclusion in psychotherapeutic interventions and meeting the needs of this underserved population.
BIOM-08. SINGLE-MOLECULE SYSTEMS FOR DETECTION OF PLASMA CIRCULATING ONCOPROTEINS IN DIFFUSE MIDLINE GLIOMA
Authors: Nir Erez, Noa Furth, Vadim Fedyuk, Jack Wadden, Rayan Aittaleb, Kallen Schwark, Madeline Miclea, Sriram Venneti, Carl Koschmann, Efrat Shema
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline glioma (DMG) is a high-risk pediatric brain tumor that has primarily been diagnosed and monitored via medical imaging (MRI) due to risks associated with re-biopsying midline brain structures. Recent advances in molecular diagnostics have improved classification and molecular characterization of DMG; these tumors are in dire need of non-invasive, molecular-based diagnostic tools to supplement serial assessments of radiographic response. Our group recently developed a single-molecule imaging platform, Epigenetics of Plasma Isolated Nucleosomes (EPINUC), to profile histone modification patterns in cell-free tumor DNA (ctDNA) from plasma of cancer patients. We developed a novel strategy for single-molecule detection of the histone mutation H3K27M, a key DMG genetic driver, by capturing mutant nucleosomes on a PEG-streptavidin coated surface and detecting them with fluorescently labeled antibodies targeting histone modifications enriched on these mutant nucleosomes. We applied this method to 46 H3K27M and 10 H3 wildtype DMG samples and found significantly higher signal in K27M samples. Using this data, we generated a predictive model of H3 status with an AUC of 0.81, sensitivity 90%, specificity 71%, and precision 73%. This test was found to be highly reproducible and rapid (60 minutes) and required less than 100 uL of plasma. We also analyzed mutant p53 protein in plasma samples from 11 p53-mutant and 4 p53-wildtype DMG patients, seeing significant separation between the two groups. We overlayed H3K27M and p53 cell-free protein results with H3.3K27M and TP53 ctDNA variant allele fraction (VAF) by digital droplet PCR (ddPCR) in serial plasma samples from n = 3 DMG patients undergoing experimental therapy. These data highlighted unique patterns of disease response by (1) MRI, (2) plasma tumor protein, and (3) plasma ctDNA. Overall, these results demonstrate the clinical potential of our platform for non-invasive and accurate detection and monitoring of levels of key oncoproteins in plasma of DMG patients.
CTNI-13. CONCURRENT INTRATHECAL CHEMOTHERAPY AND INVOLVED-FIELD RADIOTHERAPY FOR LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS: A PHASE II STUDY (NCT03082144)
Authors: Guozi Yang, Zhenyu Pan, Kunzhi Chen, Tongchao Jiang, Yuanyuan Song, Lihua Dong, Hua He, Xiaojun Ye, Min Wang, Tao Zhou
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The role of involved-field radiation therapy (IFRT) and intrathecal chemotherapy (IC) in leptomeningeal metastasis (LM) from solid tumors was gradually underestimated in the era of targeted therapy. This study was aimed to investigate the safety and effectiveness of concurrent IFRT and intrathecal methotrexate (MTX)/cytarabine (Ara-C) for LM, particularly for those who developed LM while receiving targeted therapy. METHODS Enrolled patients were randomly assigned to two subgroups (IFRT&amp;IC-MTX and IFRT&amp;IC-Ara-C), and first treated with induction IC (MTX or Ara-C) twice per week, up to 4 times. Then patients were given concurrent treatment, which consisted of IFRT (40 Gy total; 2 Gy/f) and IC (MTX 15 mg or Ara-C 50 mg, once per week). The involved field consisted of symptomatic or painful sites and disease observed on magnetic resonance imaging (MRI), including the whole brain and basis crania and/or segment of spinal canal. Primary endpoint was clinical response rate (RR). Secondary endpoints were safety and overall survival (OS). RESULTS Fifty-three patients received induction intrathecal MTX (n = 27) or Ara-C (n = 26). Forty-two patients completed concurrent therapy. Total RR was 34% (18/53). The improvement rate of neurological symptoms and KPS scores were 72% (38/53) and 66% (35/53) respectively. Adverse events (AEs) rate was 28% (15/53). Eight patients (15%, 8/53) showed grade 3-4 AEs, including myelosuppression (n = 4) and radiculitis (n = 5). Median OS was 6.5 months (95% CI, 5.3-7.7 months). Median survival for 18 patients who had clinical response was 7.9 months (95% CI, 4.4-11.4 months), and 0.8 months (95% CI, 0.08-1.5 months) for 6 patients who had LM progression. The median survival in 22 patients who received prior targeted therapy was 6.3 months (95% CI, 4.5-8.1 months). CONCLUSION Concurrent IFRT and intrathecal MTX or Ara-C was proved to be a feasible treatment option with an acceptable safety profile for LM from a common tumor entity.
IMMU-14. SINGLE CELL RNASEQ OF PBMCS FROM NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Bayli DiVita Dean, Oleg Yegorov, John Figg, Laura Falceto Font, Dan Jin, Connor Francis, Alexandra Reid, Duane Mitchell, Catherine Flores
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION A multitude of recently published papers have found immunosuppression caused by glioblastoma (GBM) is not limited to the tumor microenvironment and impacts the peripheral immune system. Our group has recently reported an expansion of granulocyte macrophage precursors, a subset of hematopoietic stem and progenitor populations (HSPCs), in glioma-bearing mice relative to healthy, age-matched controls. Thus we sought to determine if GBM causes cell fate dysfunction in CD34+ HSPCs in patients. METHODS CD34+ cells were magnetically isolated from peripheral blood of newly-diagnosed GBM patients and healthy age-matched donors and processed for single-cell RNA sequencing. CD34+ cells were magnetically isolated from peripheral blood of newly-diagnosed GBM patients and healthy age-matched donors and processed for single-cell RNA sequencing using the 10X Genomics platform. CellRanger was used for primary analysis with default parameters. After quality control removal of doublets, dead, and low quality cells automated cell type annotation was performed using the Azimuth Hubmap Consortium human bone marrow reference. The annotated single cell object was then read into R and Seurat was used for differential expression analysis and visualization. RESULTS AND CONCLUSIONS There we no significant expansions of stem and progenitor populations. GBM patient CD34+ samples had upregulation of VWF, a marker of myeloid-bias cell subset. Within the mature immune cell compartments, we observed a significant expansion of NK cells in GBM patients including 1,997 genes differentially expressed in the NK cell cluster between cohorts. This includes downregulation of SLAMF6, which triggers cytolytic activity in NK cells, in GBM patients. Upregulation of early NK cell activation markers CD69 and JUN were seen in GBM patient samples. These results strongly suggest NK are likely activated in the context of GBM, but may not be functional.
DNAR-04. MICRORNA DEGRADATION ENHANCES GLIOBLASTOMA INTRA-TUMORAL HETEROGENEITY TO AUGMENT ACQUIRED TEMOZOLOMIDE RESISTANCE
Authors: Valya Ramakrishnan, Gatikrushna Singh, Beibei Xu, Johnny Ackers, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION O6 methyl-guanine methyltransferase (MGMT) restores alkylated DNA to its undamaged form and dictates clonal evolution in response to chemotherapy. As such, MGMT is a major determinant of glioblastoma resistance to the standard-of-care chemotherapy temozolomide. miR-181d is a MGMT suppressing microRNA, whose expression inversely correlate with survival expectation after temozolomide treatment. Here, we characterize the expression of miR-181d and MGMT in response to temozolomide treatment. Method: Laboratory characterization, single cell analysis, and murine modeling RESULTS Treatment of glioblastoma cells with temozolomide (TMZ) induced a feed-forward cascade resulting in an ataxia telangiectasia and Rad3 (ATR) and polyribonucleotide nucleotidyl transferase 1 (PNPT1) dependent degradation of miR-181d. Single-cell analyses revealed such miR-181d degradation: 1) increased mean level of MGMT expression in a cell population and 2) enhanced cell-to-cell variability in MGMT expression to increase intra-tumoral heterogeneity in DNA repair capacity. This increased intra-tumoral heterogeneity enhanced glioblastoma resistance to temozolomide through a mechanism distinct from lowering the mean MGMT expression of the tumor population. Suppression of this heterogeneity by exogenous miR-181d over-expression enhanced the tumoricidal activity of temozolomide against glioblastomas. CONCLUSION We identified an interface between DNA damage response and miRNA degradation that mediate intra-tumoral heterogeneity and subsequent temozolomide resistance. This resistance mechanism is distinct from modulation of the mean MGMT expression of the population.
IMMU-19. MUTANT ISOCITRATE DEHYDROGENASE 1 IN GLIOMA CAUSES A REDUCTION IN ADENOSINERGIC PATHWAY SIGNALING WITHIN THE TUMOR MICROENVIRONMENT
Authors: Brandon McClellan, Ali Dabaja, Kaushik Banerjee, Ziwen Zhu, Marcus Barissi, Paul Oh, Abraham Wei, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2023)

Abstract Glioma is one of the most aggressive cancers and represents approximately 80% of malignant brain tumors. The majority of CNS World Health Organization (WHO) grades 2-3 gliomas and a subset of high-grade gliomas (CNS WHO grade 4) harbor mutated isocitrate dehydrogenase 1 (IDH1R132H; mIDH1). Mutant IDH1 results in the accumulation of 2-hydroxyglutarate (2HG) which elicits profound changes in the glioma transcriptome/biology. Consequently, mIDH1 glioma patients have a significantly increased median survival compared to wildtype IDH1 patients. Recent data from our lab showed that mIDH1 gliomas exhibit increased immune-reactivity of tumor-infiltrating immune cells. A critical pathway that mediates reduction of anti-tumor immune cell reactivity is the adenosinergic pathway (AP), which converts ATP into adenosine via the enzymes CD39 and CD73. Adenosine binds to adenosine receptors, A2AR and A2BR, on immune cells resulting in a decreased immunoreactivity. Although mIDH1 has been implicated in altering the AP, the extent to which the AP is affected by mIDH1 in gliomas is largely unknown. Here we used human and mouse mIDH1 glioma cells in vitro along with in vivo mIDH1 glioma mouse models to examine changes in the AP. Our results show reduced levels of the enzyme, CD73, on the surface of mIDH1 glioma cells, and the ATP concentration in the mIDH1 glioma cell growth media is lower than from wildtype IDH1 glioma cells. Additionally, we discovered that mIDH1 glioma-infiltrating macrophages have decreased expression of CD39 and A2AR compared to their wildtype IDH1 glioma counterparts. Taken together, these data suggest a reduction of the AP mediated-immune suppression in mIDH1 gliomas. Uncovering these differences in the AP provides novel insights on the use of AP inhibitors for glioma treatment, revealing whether the AP is a preferred target in specific glioma types based on the IDH1 mutation status.